Palladium-Catalyzed Picolinamide-Directed Benzylic C(sp3)?H Chalcogenation with Diaryl Disulfides and Diphenyl Diselenide

Article abstract of DOI:10.1002/adsc.202000280

The first palladium-catalyzed direct benzylic C(sp³)?H chalcogenation with diaryl disulfides and diphenyl diselenide has been established. The coupling reaction proceeds between the thioether radical and palladiumcycle intermediate. Picolinamide serves as an excellent directing group for the C?H activation of benzylic C(sp³)?H and can be easily removed. The current protocol exhibits a relatively broad substrate scope and high functional group compatibility. A mechanistic study indicates that palladium(IV) intermediate is probably formed during the course of the reaction. (Figure presented.).

Full text of DOI:10.1002/adsc.202000280

Title: Palladium-Catalyzed Picolinamide-Directed C(sp3)-H
Chalcogenation of Benzylics with Diaryl Disulfides and Diselenide
Authors: Kai Wang, Jiahao Hou, Changjun Zhang, Ke Cheng, Renren
Bai, and Yuanyuan Xie
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202000280
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10.1002/adsc.202000280
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.202((will be filled in by the editorial staff))
Palladium-Catalyzed Picolinamide-Directed Benzylic C(sp3)-H Chalcogenation
with Diaryl Disulfides and Diphenyl Diselenide
Kai Wang,a Jiahao Hou,b Changjun Zhang,a Ke Cheng,b Renren Bai,b and Yuanyuan
Xie a, b*
a Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of
Technology, Hangzhou, 310014, China.
b College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, 310014, China.
E-mail: xyycz@zjut.edu.cn (Y. Xie).
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
developed and successfully applied, such as pyridine,
Abstract. The first palladium-catalyzed direct benzylic
quinoline, O-methyl oxime, oxazoline, amide, and
C(sp3)-H chalcogenation with diaryl disulfides and
diphenyl diselenide has been established. The coupling
reaction proceeds between the thioether radical and
palladiumcycle intermediate. Picolinamide serves as an
excellent directing group for the C-H activation of benzylic
C(sp3)-H and can be easily removed. The current protocol
exhibits a relatively broad substrate scope and high
oxime.[7-9]
In the past few years, several groups have reported
picolinamide-directed and picolinamide-1-oxide-
directed C-H functionalization of phenylamine rings
with
N,N-bidentate[10]
or
N,O-bidentate[11]
coordination system. For example, wang's[11b] group
reported a cobalt-catalyzed direct C-H thiolation of
aromatic amides with disulfides, and successfully
applied this method to the synthesis of quetiapine.
functional group compatibility.
A mechanistic study
indicates that palladium(IV) intermediate is probably
formed during the course of the reaction.
Keywords: Palladium-Catalyzed; Benzylic C(sp3)-H; Our group[10d] successfully synthesized aniline
Chalcogenation; Radical Coupling
derivatives with o-trifluoromethyl by copper catalysis.
Although overwhelming majority efforts were
employed for searching novel directing groups and
bond formation reactions focus on C(sp2)-H bonds,
functionalization of C(sp3)-H bonds has also enjoyed
remarkable evolution. According to previous reports,
the chelating effect enhances the metal reactivity,
especially towards less reactive C(sp3)-H bonds.[12] In
particular, palladium-catalyzed functionalization of
C(sp3)-H bonds has been proved effective in the
synthesis of various organic molecules. [13] In 2012,
Zhang’s group[14a] reported an efficient palladium-
catalyzed arylation/oxidation of benzylic C-H bond
via a C(sp3)-H activation with the N,N-bidentate
coordination system. Furthermore, the group reported
another palladium-catalyzed C(sp3)-H acetoxylation
with the same guiding group to form benzyl esters.
Similar acetoxylation works were reported by
Chen’s[15a] and Huang’s group.[15b] (Scheme 1)
Introduction
As an important building block of active groups,
aryl chalcogenide skeletons are ubiquitous in
biologically active natural products, as well as in
areas of pharmaceuticals and material science.[1]
Based on this, series of work had been done to
synthesize thioethers.[2] However, there still remains
the problem of preparing the starting halobenzenes,
resulting sulfenylated and halogenated by-products in
the conventional C-S cross-coupling of aryl halides
with thiols.
Over the recent decades, mild and selective
protocol via transition-metal-catalyzed direct C-H
bonds functionalization has become a novel and
efficient strategy in the construction of C-X bond (X
= C, N, O, S).[3-6] Among all reported methods, the
chelation assisted directing group strategy has gained
increasing attention for site-selective C-H activation
and sequences types of directing groups were
1
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10.1002/adsc.202000280
Advanced Synthesis & Catalysis
tert-butyl perbenzoate (TBPB), Na2S2O8 and K2S2O8
found to be superior to the others (Table 1, Entries
17-19). Next, when the additive was changed to
K2CO3, Na2CO3 andKOAc the yields were changed to
35%, 39% and 71% (Table 1, Entries 20-22). After
that, with the removal of DTBP or KOAc, the yields
were reduced to 31% and 42% (Table 1, Entries 16,
22). Further screening in temperature as well as
catalyst dosage did nothing to enhance the product
yield (Table 1, Entries 23-24).
Table 1. Reaction optimizationa
Table 1. Reaction optimization a
Scheme 1. Pd-catalyzed picolinamide-directed
benzylic C(sp3)-H bond functionalizations
As can be seen from above, most palladium-
catalyzed picolinamide-directed benzylic C(sp3)-H
functionalizations were mainly focused on the
construction of C-C and C-O bonds, while
chalcogenation had rarely been reported. Considering
the importance of aryl chalcogenide, it is particularly
important to develop a convient synthetic method for
these compounds.
Herein, we report a palladium-catalyzed direct
benzylic C(sp3)-H chalcogenation with diaryl
disulfides and diphenyl diselenide to afford the
desired products in moderate to excellent yields under
mild conditions.
Yield
[%]b
Entry
Catalyst
Oxidant
Additive
Solvent
1
2
Co(OAc)2
CoBr2
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
TBPB
TBHP
Na2S2O8
K2S2O8
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
K2CO3
Na2CO3
KOAc
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
p-xylene
DMSO
45
40
3
Co(acac)2
NiCl2
trace
N.R
N.R.
N.R.
65(0)c
43
4
5
CuBr2
6
Cu(OAc)2
Pd(OAc)2
Pd(TFA)2
Pd(dbc)2
PdCl2
7
8
9
37
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
23
Pd(PPh3)4
Pd(PPh3)2Cl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
27
Results and Discussion
29
53
41
With the topic decided, we initiated the
investigation by conducting the direct thiolation of N-
(o-tolyl)picolinamide (1a) and 1,2-diphenyldisulfane
(2a) as a model reaction (Table 1). To our delight, the
reaction was allowed to run by using Co(OAc)2 as
catalyst in the presence of DTBP and NaOAc at
120oC in toluene for 12 h, and the desired N-(2-
((phenylthio)methyl)phenyl)picolinamide (3a) was
obtained in 45% yield (Table 1, Entry 1).
Encouraged by this result, different metal catalysts
including CoBr2, Co(acac)2, NiCl2. CuBr2, Cu(OAc)2
and Pd(OAc)2 were investigated. Among these
catalysts, Pd(OAc)2 showed best catalytic capacity
45
45(31)d
36
N.R.
N.R.
35
DMF
Toluene
Toluene
Toluene
Toluene
Toluene
39
71(42)e
33f
67g
KOAc
KOAc
[a] Reaction conditions: 1a (0.2 mmol), 2a (0.6 equiv.), catalyst (10 mol%),
oxidant (2.0 equiv.), additive (2.0 equiv), solvent (2.0 mL), stirred at 120
oC, under air, 16 h.
Isolated yields.
Without catalyst.
Without
[b]
[c]
[d]
and gave the yield of target product 3a in 65% (Table oxidant. [e] Without additive. Pd(OAc)2 (5 mol%) Stirred at 100oC.
[f]
[g]
TBHP = tert-butyl hydroperoxid. DTBP = Di-tert-butyl peroxide. TBPB =
1, Entries 2-7). When the catalyst was removed, no
product was isolated at all (Table 1, Entry 7). Since
tert-butyl perbenzoate.
then, different palladium catalysts like Pd(TFA)2,
With the aforementioned optimized reaction
Pd(dbc)2, PdCl2, Pd(PPh3)4 and Pd(PPh3)2Cl2 were
protocol in hand, we then screened the disulfides of
studied, the results showed that Pd(OAc)2 has the best
this transformation (Table 2). An array of diaryl
catalytic performance for this reaction (Table 1,
disulfides comprising either electron-donating groups
Entries 8-12). A follow-up study on the screening of
(-Me and -OMe) or electron-withdrawing groups (-Cl,
oxidants verified that the di-tert-butyl peroxide
-Br and -NO2) could tolerate the reaction conditions,
(DTBP) has better promoter action than other
giving the desired products in 32% to 73% (Table 2,
oxidants such as tert-butyl hydroperoxide (TBHP),
3a–3f, 3j-3l). At the same time, the position of the
2
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10.1002/adsc.202000280
Advanced Synthesis & Catalysis
substituent also had a significant effect on the reaction. corresponding sulfone 5 which was first synthesized
When the substituents were in the ortho-position of (Scheme 2).
the phenyl ring, the reaction could rarely take place
(Table 2, 3g-3i), indicating that steric factors
significantly reduced the reaction potency. Further
studies were carried out using arylamine derivatives
with methyl, halogen and nitro groups manifesting
that substituted arylamines had lower reactivity
(Table 2, 3m-3r). Ulteriorly, the reaction of
arylamine bearing meta-methyl and para-nitro groups
could not proceed, simultaneously, none desired
product was obtained when 2-ethylaniline was used,
which showed that steric effect and strong electron-
withdrawing group had obvious influence on the
reaction activity (Table 2, 3o, 3r and 3w). Follow
investigation of various kinds of directing groups
were performed and manifested that the changes in
guiding groups have no conspicuous effect on the
reaction (Table 2, 3s-3v).
Scheme 2. Removal of the directing group and the
preparation of sulfone.
In order to further expand the applicability of the
reaction, different selenium ethers were also screened.
Nevertheless, the stability of the substituted selenium
1
ether products was so poor that H NMR spectra was
not good. However, to our delight, diphenyl
diselenide could provide the desired products 7a and
7b in good yields and high purity whether the
directing group was 2-pyridyl or 2-isoquinolyl
(Scheme 3).
Table 2. Substrate scope of the direct thiolation a,b
Scheme 3. Synthesis of 7 with diphenyl diselenide.
Following studies were implemented with
thiophenol as raw material showing that thioether
could also be synthesized by the oxidation system of
I2 and DMSO (Scheme 4, 3c).
Scheme 4. Synthesis of 3c using 4-methoxy-
benzenethiol as starting material.
To gain more insights into the reaction mechanism,
a series of control experiments were conducted
(Scheme 5). Primarily, we found that none desired
products were detected when radical scavengers such
as TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) or
BHT (butylated hydroxytoluene) were used. Similarly,
no desired products were obtained when 1a was
replaced by 9a~9f, which indicated that
chalcogenation could be attributed to a synergistic
effect causing by the mutual effect between the
pyridine nitrogen atom and amide group. Finally, the
thioether radical was successfully captured by ethene-
1,1-diyldibenzene, and the compound 10 was detected
by ESI-HRMS.
[a]
Reaction conditions: 1 (0.2 mmol), 2 (0.6 equiv.),
Pd(OAc)2 (10 mol%), DTBP (2.0 equiv.), KOAc (2.0
o
equiv.), toluene (2.0 mL), stirred at 120 C, under air,
16 h. [b] Isolated yields.
After relevant investigation, we found that guiding
group was easy to be removed to obtain 2-(((4-
methoxyphenyl)thio)methyl)anilinethe 4. Oxidation
of sulfides product 3c resulted in the production of
3
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10.1002/adsc.202000280
Advanced Synthesis & Catalysis
the next catalytic cycle. However, based on previous
reports [3d, 9j-m], the Pd(II)/Pd(III) catalytic cycle could
not be ruled out either.
Conclusion
In summary, we have developed the first
palladium-catalyzed direct benzylic C(sp3)-H
chalcogenation with diaryl disulfides and diphenyl
diselenide by employing a bidentate system. This
protocol testified a comprehensive substrate scope,
high-efficiency and functional group tolerance. The
amide auxiliary was easily removable after the
transformation.
Scheme 5. Mechanistic studies
Experimental Section
Based on the aforementioned experiments and
previous related reports,[3d, 9j-m, 10g-h, 11b, 14b] a proposed
mechanism was illustrated in Scheme 6.
General procedure for the synthesis of N-(2-
((phenylthio)methyl)phenyl)picolinamide (3a)
A mixture of 1a (42.4 mg, 0.2 mmol), 2a (26.1 mg,
0.6 eq.), Pd(OAc)2 (4.4 mg, 10 mol%), KOAc (39.2
mg, 2.0 eq.) and DTBP (58.4 mg, 2.0 eq.) in toluene
(2.0 mL) was placed in a Schlenk tube and stirred at
120℃ under air atmosphere for 16.0 h. Then the
mixture was cooled to room temperature and
concentrated under vacuum after filtration. The
product 3a was purified by silica gel column flash
chromatography using PE/AcOEt (40:1) as an eluent.
General procedure for the synthesis of N-(2-
((phenylselanyl)methyl)phenyl)picolinamide (7a)
A mixture of 1a (42.4 mg, 0.2 mmol), 4a (37.6 mg,
0.6 eq.), Pd(OAc)2 (4.4 mg, 10 mol%), KOAc (39.2
mg, 2.0 eq.) and DTBP (58.4 mg, 2.0 eq.) in toluene
(2.0 mL) was placed in a Schlenk tube and stirred at
120℃ under air atmosphere for 16.0 h. Then the
mixture was cooled to room temperature and
concentrated under vacuum after filtration. The
product 7a was purified by silica gel column flash
chromatography using PE/AcOEt (40:1) as an eluent.
Scheme 6. Plausible mechanism with palladium
catalyst
Initially,
N,N-bidenate
ligand
of
N-(o-
tolyl)picolinamide 1a coordinates with Pd(OAc)2 to
produce complex (A), which undergoes a reversible
C-H bond activation to generate palladacycle species
(B). Disulfides 2a affords thioether radical in the
presence of DTPB under heating conditions, which
further couples with intermediate (B) to furnish the
palladium(IV) complex (C). Then, palladium
phenylsulfide (D) is afforded via the reductive
elimination of (C) with C-S bond formation. Next,
ligand exchange of (D) with AcOH provides the
palladium(II) species (E) and benzenethiol (detected
by ESI-HRMS, see Supporting Information VI). This
step is essential in the catalytic process. Finally,
protonation of intermediate (E) by AcOH delivers the
desired product 3a and regenerates Pd(OAc)2 for the
Acknowledgements
This work was supported by the National Natural
Science Foundation of China, NSFC (No. 21978273
and 21576239) and National Key R&D Program of
China (No. 2018YFC0214100).
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10.1002/adsc.202000280
Advanced Synthesis & Catalysis
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6
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Advanced Synthesis & Catalysis
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Palladium-Catalyzed
Picolinamide-Directed
Benzylic C(sp3)-H Chalcogenation with Diaryl
Disulfides and Diphenyl Diselenide
Adv. Synth. Catal. Year, Volume, Page – Page
Kai Wang, Jiahao Hou, Changjun Zhang, Ke
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